Our project is directly responsive to the program objectives by applying high throughput technologies to isolate small molecules capable of disrupting or modifying the communication between the idiotypic T cell receptor (TCR) and CD3, its obligate signaling partner. Structural and biophysical studies have taught us that the TCR/CD3 interaction was of very low affinity and very sensitive to minor alterations, making it a perfect target for small molecules development. We have created and optimized a fluorescence polarization assay amenable to high throughput screen using recombinant TCR molecules labeled with fluorophore on single cysteine mutants. A proof of concept campaign isolated 6 compounds that showed specificity for TCR binding and were capable of disrupting specifically the TCR/CD3 communication of T cells without affecting T cells signaling. All 6 hits were inhibiting T cell signaling of both MHC class I- and MHC class II-restricted T cells and as such could be categorized as immunosuppressive compounds. Our goals are to identify chemical probes that will allow us to further our basic knowledge of T cell activation and to discover, in that same process, new families of immunomodulators. Indeed, new immunosuppressive drugs are much needed in the field of transplantation and autoimmunity, because of the toxicity of the current treatments. Because of the strategy that we have developed, it is also possible that some chemical fragments that we will isolate, will exhibit immunostimulatory properties. This class of drugs, e.g. general immunostimulants, does not exist yet and would fill a huge gap to combat the immunosuppression of cancer and chronic infectious diseases. Our project illustrates the capabilities of integration that our institute offers by having side-by-side specialists in chemistry, structural biology, biophysics, chemical biology, cellular immunology and animal immunology working together towards a clearly defined goal of translating basic science into the development of new therapeutics.